A major objective of the proposed program is to identify pivotal systemic and local factors involved in the development of inflammation and fibrosis of the renal parenchyma, and to elucidate the mechanisms by which these factors affect target cells within the kidney. Our overall hypothesis is that tubulointerstitial inflammation and fibrosis has a fundamental role in the progression of chronic renal disease. A variety of renal diseases of glomerular and non-glomerular origin lead to fibrosis of the tubulointerstitium. This program will utilize concepts and techniques of cell and molecular biology to investigate alterations in renal structure and function due to inflammation and fibrosis. The proposed studies will encompass the use of normal mice and transgenic mice (knockout for TNFR1, TNFR2, AT1, AT2, osteopontin and beta3). Additional mutants will be added by purchase (such as SOD1 transgenics from Jackson Laboratory) or prepared in the Core facility. Cultures of primary proximal tubule cells and of kidney fibroblasts will be used. We will also test promoter activity in vitro (transfection of cells in culture). The studies proposed in the four projects represent logical extensions of work currently in progress in the different laboratories. The four projects and two cores will examine: the mechanisms of tubulointerstitial disease in obstructive disease in obstructive nephropathy (Project 1); the role of motility factors in renal fibrogenesis (Project 2); the mechanisms of metalloproteinase expression by oxidant stress (Project) 3 and Project 4 will focus on fibroblast activation in urinary obstruction. In addition two cores: an Administrative Core (Core A) and a Laboratory Core (Core B) will provide services and expertise in certain techniques and assays to the different component projects and investigators of this Program. The ultimate goal of this program is to develop strategies to forestall the progression of chronic renal disease.